Author:
Jillian Simard, MD,1 Christopher Melani, MD,2
Rahul Lakhotia, MD,1
Michail S. Lionakis, MD
ScD,*,3
Stefania Pittaluga, MD PhD,4
James D. Phelan, PhD,*,1 Jagan R. Muppidi, MD
PhD,*,1
Lydia L. Chou, CRNP,*,1
Matthias Holdhoff, MD PhD,*,5 Michael Glantz, MD PhD,*,6
John A. Butman, MD PhD,*,7 Andrea Nicole Lucas, RN,*,8
Seth M. Steinberg, PhD,*,9
Elaine
S. Jaffe, MD,4
Louis M. Staudt, MD PhD,1
Wyndham H. Wilson, MD PhD,1 Mark Roschewski, MD10
Author address:
1
Lymphoid Malignancies Branch, Center for Cancer Research,
National Cancer Institute, National Institutes of Health, Bethesda, MD
2
Lymphoid Malignancies Branch, Center for Cancer Research,
National Cancer Institute, National Institutes of Health, Baltimore, MD
3
Laboratory of Clinical Infectious Diseases, National Institute of Allergy
and Infectious Diseases, National Institutes of Health, Bethesda, MD
4
Laboratory of Pathology, Center for Cancer Research, National
Cancer Institute, National Institutes of Health, Bethesda, MD
5Department of Neuro-Oncology, Johns Hopkins Cancer Center, Baltimore, MD
6Department of Neurosurgery, Penn State College of Medicine, Hershey, PA
7Radiology and Imaging Sciences, Clinical Center, National
Cancer Institute, National Institutes of Health, Bethesda, MD
8
Lymphoid Malignancies Branch, Center for Cancer Research,
National Cancer Institute, National Institutes of Health, Bethesda, MD
9
Biostatistics and Data Management Section, National Cancer Institute, National Institutes of Health, Bethesda, MD
10Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD
Full conference title:
62nd American Society of Hematology Annual Meeting and Exposition
Date: 5 December 2020
Abstract:
Background: Secondary CNS B-cell lymphomas (SCNSL) are aggressive lymphomas with a very poor
prognosis. Genetic subtypes of DLBCL with CNS tropism are enriched for chronic active B-cell receptor
signaling and may respond to BTK inhibition (BTKi). CLL, MCL, and transformed lymphomas can also
involve the CNS and are BTKi responsive. TEDDI-R achieves durable remissions in relapsed/refractory
primary DLBCL of the CNS (PCNSL) but the profile of SCNSL tumors that are ibrutinib-responsive is
unknown. We present preliminary results from a response-adapted trial of ibrutinib with TEDD-R in
SCNSL.
Methods: Pts with aggressive B-cell lymphomas with secondary CNS involvement are eligible if age
≥18 and adequate organ function. Pts must have relapsed after frontline therapy or can be untreated if
brain parenchyma involved. Prior BTKi is allowed, but HIVinfection and EBV+
lymphomas are excluded.
Baseline tests include brain MRI, FDG-PET brain and body, CSF with flow cytometry, Ommaya, and eye
exam. Pts receive isavuconazole starting at 200mg BID x 3d prior to ibrutinib to prevent fungal infections
associated with TEDDI-R and then 200mg daily unless ibrutinib stopped. Pts first receive ibrutinib 560mg
daily x 14d in a window. If ≥20% reduction after ibrutinib, pts receive TEDDI-R for 4 cycles every 21d with
IT cytarabine. Pts with <20% reduction after ibrutinib receive TEDD-R without ibrutinib for 4 cycles every
21d with IT cytarabine. No consolidation or maintenance is permitted. Surveillance for fungal infections
includes chest CT after each cycle along with Beta-D glucan and aspergillus galactomannan in blood
and CSF. Brain MRI and CT scans are performed after cycles 1, 2, and 4 to determine response. All
remissions by MRI are confirmed with FDG-PET and CSF analysis. Surveillance brain MRI and CT scans
are q3m for 1y, q4m x 1y, q6m x 1y, then annually.
Results: 16 pts with a median age 67 (range 40-79) enrolled between June 2019 and July 2020. 15
(94%) pts had DLBCL comprising 9 (60%) non-GCB, 5 (33%) GCB, and 1 (7%) transformed from MZL.
One pt had plasmablastic lymphoma. Eight (50%) pts had a MYC-rearrangement including 4 (25%) with
both MYC and BCL2 or BCL6 rearrangements. Eight (50%) pts had isolated CNS disease and 8 (50%)
had synchronous CNS and peripheral disease. All pts relapsed after a median of 2 (range 1-4) prior
therapies and all (100%) pts received prior anthracycline. Seven pts (44%) had prior CNS prophylaxis
and 8 pts (50%) had prior HD-MTX based salvage therapy. Toxicity was evaluated across 35 cycles. G3
and G4 neutropenia occurred in 49% and 29% of cycles, respectively, while febrile neutropenia occurred
in 9% of cycles. The median (range) duration of neutropenia was 6 (1-13) days. Five (14%) cycles were
complicated by ≥G3 infection, but no opportunistic infections (including Aspergillus) were observed. One
pt developed a bacterial infection during cycle 1 and died. G3 and G4 thrombocytopenia occurred in 34%
and 23% of cycles, respectively, and 1 pt developed G3 hematuria. G3 mucositis occurred in 9% of cycles
and palmar-plantar-erythrodysesthesia led to dose reductions of liposomal doxorubicin in 5 (36%) pts. Of
15 pts who completed the 14d ibrutinib window and were evaluable, 8 (53%) were ibrutinib-responsive
and 7 (47%) were ibrutinib-resistant (Figure 1). Clinical responses were concordant across anatomic
compartments; of 8 pts with both CNS and peripheral disease, 5 (63%) responded to ibrutinib in both
compartments while 3 (37%) did not respond in either compartment. All 8 ibrutinib responders had a nonGCB phenotype and six (75%) achieved CR. One died of treatment-related toxicity after a PR and 1 is still
on therapy. Only two (29%) pts with ibrutinib-resistant tumors achieved PR and none have achieved CR.
After a median follow-up of 5.1m, a landmark analysis starting after the ibrutinib window demonstrated
the PFS for pts with ibrutinib-responsive compared to ibrutinib-resistant tumors was not reached vs. 0.9m
(95% CI: 0.1-2m)(p=0.002)(Figure 2).
Conclusions: Patients with SCNSL tumors that are ibrutinib-responsive achieve a high rate of complete
response to TEDDI-R in both CNS and peripheral disease. Patients with tumors that are ibrutinib-resistant
also respond poorly to TEDD-R. Toxicity is mainly hematologic, and no Aspergillus infections have occurred with the use of isavuconazole prophylaxis. Updated clinical results from this ongoing study
(NCT03964090) and will be presented at the meeting.
Conference Year: 2020
Link to conference website: https://www.hematology.org/meetings/annual-meeting/past-and-upcoming-meetings
Tables:
URL Conference abstract: